1. Field of the Invention
This invention relates primarily to novel synthetic procedures and compounds which are useful in the synthesis of a range of mevinic acids.
2. Description of the Prior Art
A number of mevinic acids which can formally be regarded as decalin derivatives, have been reported to be potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia.
Thus W F Hoffman et al (J. Med. Chem., 29, 849-852 (1986)) have reported the synthesis and testing of a compound now known as simvastatin, having the structure ##STR3##
EP-A-0251625 (Inamine) discloses compounds of structure ##STR4## where R is similar to the corresponding group in the compound described above, R.sup.1 is a group of formula CH.sub.2 OH, CH.sub.2 OCOR.sup.3, CO.sub.2 R.sup.4 or CONR.sup.6 R.sup.7 wherein R.sup.3, R.sup.4, R.sup.6 and R.sup.7 can cover a range of alkyl, alkoxy or aryl groups, an the dotted lines represent single or double bonds.
The compound disclosed have been generally obtained by fermentation of a suitable microorganism, or have been chemically derived from compounds obtained from such fermentations. However, a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.
WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids. Specifically, this publication describes the synthesis of compounds of the general formula: ##STR5## wherein: R.sup.1 represents a C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl(C.sub.1-8)alkyl, C.sub.2-8 alkenyl, or C.sub.1-6 alkyl substituted phenyl group;
R.sup.2 represents a C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, group or a C.sub.1-5 alkyl, C.sub.2-5 alkenyl, or C.sub.2-5 alkynyl group substituted with a substituted phenyl group; PA0 R.sup.3 represents a hydrogen atom or a substituent R.sup.4 or M; PA0 R.sup.4 represent a C.sub.1-5 alkyl group, or a C.sub.1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino; PA0 R.sup.5 represents a hydrogen atom or a methyl or ethyl group, except that when R.sup.2 is methyl then R.sup.5 is not methyl; PA0 M represent a cation capable of forming a pharmaceutically acceptable salt; PA0 Q represents C.dbd.O or CHOH; and PA0 each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond. PA0 R.sup.2 represents C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl(C.sub.1-8)alkyl, C.sub.1-8 hydroxyalkyl, C.sub.1-8 alkylthio, phenyl or substituted phenyl; PA0 R.sup.3 represents C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CO.sub.2 (C.sub.1-8)alkyl, CO.sub.2 (C.sub.2-8)alkenyl, C.sub.1-8 alkylthio, (C.sub.1-2) alkyl CO.sub.2 (C.sub.1-8)alkyl or C.sub.1-8 aldehydroalkyl where the aldehyde function is protected by a suitable protecting group (for example, an acetal such as a dimethyl acetal); PA0 R.sup.4 represents a hydrogen atom, C.sub.1-8 alkyl or C.sub.2-8 alkenyl; PA0 Z represents a group (CH.sub.2).sub.n or a branched alkyl chain; PA0 n is 0 to 8; PA0 and each of a, b and c is independently a single or a double bond; PA0 wherein R.sup.1 is as defined in general formula I; PA0 in the presence of meal ions such as chromium ions. PA0 R.sup.2 represents C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl or C.sub.1-8 hydroxyalkyl; PA0 R.sup.3 represents CO.sub.2 C.sub.1-8 alkyl; PA0 R.sup.4 represents a methyl group; PA0 Z is (CH.sub.2).sub.n ; PA0 n is 0; and PA0 a and b are single bonds and c is a double bond; and PA0 in compounds of formula I, R.sup.1 is a methyl group. PA0 X is (CH.sub.2).sub.m or a branched alkyl chain; and m is 0 to 2 using a reducing agent such as lithium aluminium hydride or lithium borohydride or alkyl derivatives of either of them. A particularly suitable reducing agent for the reaction is lithium triethylborohydride and it is preferred that the reaction be carried out in a solvent such as tetrahydrofuran at a temperature of between -20.degree. C. and room temperature. The reaction proceeds particularly satisfactorily at about 0.degree. C. PA0 by oxidation with a mild oxidizing agent which may be for example pyridinium dichromate in the presence of activated molecular sieves and acetic acid. The reaction can be performed in any suitable inert, aprotic solvent such as dichloromethane and will generally be carried out under an inert atmosphere such as argon. PA0 R.sup.6 is a C.sub.1-8 alkyl straight chain alkyl group; PA0 by selective reduction of the ester group attached to the 6-position of the decalin ring system. PA0 R.sup.2 represents C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl or C.sub.1-8 hydroxyalkyl; PA0 R.sup.3 represents CO.sub.2 (C.sub.1-8)alkyl; PA0 R.sup.4 represents a methyl group; PA0 Z is (CH.sub.2).sub.n ; PA0 n is 0; and PA0 a and b are single bonds and c is a double bond; and PA0 in compounds of general formula VI, R.sup.6 is methyl. PA0 ethyl (1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro-6-methoxycarbonyl-2-methyl-8-(2,2-dimethy lbutyryloxy) napthalene-1-carboxylate. PA0 ethyl (1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro-6-methoxycarbonyl-2-methyl-8-(2,2-dimethy lbutyryloxy) napthalene-1-carboxylate. PA0 by acrylation with an appropriate acylating agent, which may be an acid halide of general formula VIIa EQU R.sup.2 COX (VIIIa) PA0 wherein R.sup.2 is as defined in general formula I and X is Cl or Br. PA0 wherein R.sup.2 as is defined in general formula I. alternatively, and particularly in cases where compounds of general formulae VIIIa and VIIIb are unstable, a carboxylic acid of general formula VIIIc may be used as an acylating agent. EQU R.sup.2 CO.sub.2 H (VIIIc) PA0 wherein R.sup.2 is as defined in general formula I. The reaction should preferably be carried out in the presence of a coupling agent such as 1,3-dicyclohexylcarbodiimide in pyridine or in an aprotic solvent such as tetrahydrofuran. Preferably, an activating agent such as diemthylaminopyridine is also present and a base such as triethylamine may also be used. A particularly suitable acylating agent for this reaction is dimethylbutyryl chloride in pyridine and the reaction temperature is ideally abut 90.degree. C. PA0 R.sup.2 represents a C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, group or a C.sub.1-5 alkyl, C.sub.2-5 alkenyl, or C.sub.2-5 alkynyl group substituted with a substituted phenyl group; PA0 R.sup.3 represents a hydrogen atom or a substituent R.sup.4 or M; PA0 R.sup.4 represents a C.sub.1-5 alkyl group, or a C.sub.1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino; PA0 R.sup.5 represents hydrogen atom or methyl or ethyl group, except that when R.sup.2 is methyl then R.sup.5 is not methyl; PA0 M represents a cation capable of forming a pharmaceutically acceptable salt; PA0 Q represents C.dbd.O or CHOH; and PA0 each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; PA0 the method comprising converting a compound of general formula VII to a compound of general formula IV by the method described above, followed by converting a compound of general formula IV to a compound of general formula IX or X by an appropriate method. PA0 (1S, 2S, 4aR, 6S, 8S, 8aS, 4'R, 6'R)-6'-(2-(1,2,4a,5,6,7,8,8a-octohydro-2-methyl-8-[(2",2"-dimethyl-1"-oxo butyl)-oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-ethyl}-tetrahydro-4'-hydrox y-2H-pyran-2'-one
In particular the document describes the synthesis of (1S, 2S, 4aR, 6S, 8S, 8aS, 4'R, 6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobut yl)-oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H -pyran-2'-one which has the structure: ##STR6## Pioneering as the work disclosed in WO-A-9100280 is, however, there is still room for further improvement in the synthetic methodology used, not least to enable the synthesis to be readily scaled up from the laboratory to pilot plant or production scale.
One of the steps used in the synthesis is the conversion of an aldehyde substituent on the decalin ring to an alkenyl substituent. In WO-A-9100280, this conversion is carried out either by a route involving sulphone derivatives and mercury amalgam, which because of its high toxicity is obviously unsuitable for use on a large scale, or by the Wittig reaction. Although the Wittig reaction proceeds satisfactorily, the reaction temperature must be kept at about -78.degree. C. to avoid decomposition of the ylid starting material.
It has now been found that other conditions and reactants may be used to enable the reaction to proceed at or near room temperature.